This invention relates to a method of treatment for interstitial cystitis. More particularly, this invention is directed to the administration of an inhibitor of neurohormonal activation of bladder mast cell secretion as a methods of treatment for interstitial cystitis.
Interstitial cystitis is a urologic condition of unknown etiology that predominantly (90%) affects young and middle-aged females although men and children can also be affected. It is characterized by irritative voiding symptoms, symptoms of urinary urgency, frequency, dysuria, nocturia, and suprapubic or pelvic pain related to and relieved by voiding. A great number of interstitial cystitis patients also experience headaches, gastrointestinal and skin problems which suggest that interstitial cystitis may represent the end organ (bladder) response of a systemic condition affected by many heterogeneous stimuli triggering a common denominator, the mast cell.
The ulcerative form of the disease is uncommon, accounts for ten percent (10%) of cases and is associated with a reduced bladder capacity and the presence of ulcers and scars. The more common form of the disease is the early or non-ulcerative variety associated with normal bladder capacity and an absence of ulcers. These two forms of the disease may have different etiologies and pathologic characteristics. Symptoms of interstitial cystitis are usually present for many years before diagnosis and they usually peak and stabilize within a few years of diagnosis. Progression of the disease often leads to social and emotional crippling. The pain and frequency may interfere with an individual's ability to work and to socialize, and the nocturia may lead to chronic loss of sleep.
The pathology and pathogenesis of interstitial cystitis have not been clearly elucidated. Theories proposed include infection, vascular obstruction, autoimmunity, inflammatory, neurogenic and endocrine causes. The role of the mast cell in the bladder wall and the bladder surface protective glycosaminoglycan (GAG) layer are current areas of research interest. Recent evidence indicates that bladder mast cells may be activated without necessarily an increase in numbers. Histamine and other mediator release in the bladder wall of interstitial cystitis patients may be a pathogenetic mechanism for the causation of the disease. In spite of the description of increased numbers of mast cells in the bladder wall, there is no agreement regarding whether the mast cell is a consequence of interstitial cystitis or a pathogenetic factor in its causation. However, it appears that mast cells are uniformly activated and have secreted their mediators.
Past treatments for interstitial cystitis have included the administration of antihistamines, sodium pentosanpolysulfate, dimethylsulfoxide, steroids, tricyclic antidepressants and narcotic antagonists. However, these methods have not been successful (Sant, G. R. Interstitial cystitis: pathophysiology, clinical evaluation and treatment. Urology Annal 3:171-196, 1989).
The histamine-1 receptor antagonist, pyribenzamine, was first reported in 1958 (Simmons, J. L. and Bunce, F. L. On the use of an antihistamine in the treatment of interstitial cystitis. American Surgery 24:664-667, 1958) for use in the treatment of interstitial cystitis. The oral administration of 50 mg of pyribenzamine three times daily was said to produce some symptomatic improvement. However, the duration of the response was variable and this work was never duplicated later.
Oral sodium pentosan polysulfate (Elmiron) has been used in the clinical treatment of interstitial cystitis (Mulholland, S. G. Hanno, P., Parsons, C. L., Sant, S. R, Staskin, D. R. Pentosan polysulfate sodium for therapy of interstitial cystitis. Urology 35:552-558, 1990). This compound is a synthetic analogue of a sulfonated glycosaminoglycan, which is the natural compound found in the surface mucin of the bladder mucosa. In interstitial cystitis this protective mucin layer appears to be lost. Oral or intravesical administration of this preparation has been said to replace the protective surface mucin. A disadvantage of this type of treatment is that the drug must be taken numerous times per day because of its short duration. Another disadvantage is that the dosage administered must be high because only a small amount of the drug will reach the site of treatment, since it is primarily liver-metabolized.
Intravesical injections of dimethylsulfoxide (DMSO) have also been used to treat interstitial cystitis (Sant, G. R. Intravesical 50% dimethyl sulfoxide (RIM50-50) in treatment of interstitial cystitis. Supplements to Urology 29:17-21, 1987). This method of treatment involves extreme discomfort and inconvenience because it requires the anesthetization and catheterization of the urethra. Most patients experience a garlic-like breath odor and a similar taste in their mouths due to pulmonary excretion of a small percentage of the DMSO as dimethyl sulfide. Bladder spasms and irritability may be experienced with DMSO treatment, as well as urethral burning during voiding which necessitates treatment with oral anticholinergics.
Steroids have been used both intravesically and systemically because their anti-inflammatory action reduces bladder wall inflammation. The improvements obtained with steroid treatment are short-lived, many patients relapse and side effects, such as fluid retention and osteoporosis are common. The unpredictable response and the risk of side effects from prolonged therapy limit the use of steroids.
Tricyclic antidepressants have recently been used to treat patients with interstitial cystitis with about 30% responding. However, patients treated with amitriptyline, the only tricyclic on which data are available, have experienced troublesome side effects such as hypotension, tachycardia, anxiety, or palpitations (Hanno, P. M., Buehler, J., Wein, A. J. Use of amitriptyline in the treatment of interstitial cystitis. Journal of Urology 141:846-848, 1989).
Also utilized in the past have been the subcutaneous and intravesical injection of heparin, intravesical injection of silver nitrate and bladder distension. The inconvenience and the potential side effects of these methods do not make them acceptable therapeutic approaches. Therefore, the need exists for a method of treatment of interstitial cystitis that is safe and effective, which need is met by the method of the present invention.
U.S. Pat. No. 4,268,518 (May 19, 1981) discloses that compounds related to 1,3-bis (2-carboxy chromon-5-yloxy)-2-hydroxypropane may be used for the treatment of cystitis in general. However, such compounds do not inhibit secretion from mucosal mast cells (Pearce, F. L., Befus, A. D., Gauldie, J., Bienenstock, J. Effects of antiallergic compounds on histamine secretion by isolated intestinal mast cells. Journal of Immunology 126:2481-2486) which are an important component of the pathophysiology of interstitial cystitis. Moreover, such compounds do not block neurohormonal activation of mast cell secretion.
U.S. Pat. No. 4,877,791 (Oct. 21, 1989) discloses the daily administration to patients suffering from interstitial cystitis of the narcotic antagonists, nalmefene or naltrexone. The disadvantages of utilizing narcotic antagonists in the treatment of interstitial cystitis are: a) that they may block mast cell activation by only one trigger (endorphins) not operating in this disease, b) will cause dysthymia, which is characterized by lack of pleasure appreciation and sensation, c) blockade of endogenous opioids (endorphins) which help alleviate the pain and d) inability to use opioids (eg. morphine or demerol) for additional treatment of pain associated with IC. In other words, long-term therapy may lead to more pain.